New efficient route to an advanced precursor of the AB spiroketal of spongistatins

Article abstract of DOI:10.1021/ol702326x

A sequence of highly diastereoselective functionalizations allowed transformation of a meso-methylenebis(cyclohept-3-ene-1,6-diyl diester) into an advanced precursor of the AB spiroketal of spongistatins. This route illustrates the potential of this bis-c

Full text of DOI:10.1021/ol702326x

ORGANIC
LETTERS
2007
Vol. 9, No. 24
5107-5110
New Efficient Route to an Advanced
Precursor of the AB Spiroketal of
Spongistatins
Sylvain Favre, Sandrine Gerber-Lemaire,* and Pierre Vogel
Laboratory of Glycochemistry and Asymmetric Synthesis, Ecole Polytechnique
Fe´de´rale de Lausanne (EPFL), Batochime, CH-1015 Lausanne, Switzerland
sandrine.gerber@epfl.ch
Received September 25, 2007
ABSTRACT
A sequence of highly diastereoselective functionalizations allowed transformation of a meso-methylenebis(cyclohept-3-ene-1,6-diyl diester)
into an advanced precursor of the AB spiroketal of spongistatins. This route illustrates the potential of this bis-cycloheptene derivative for the
synthesis of a key fragment of complex bioactive natural compounds.
Spiroketals and, in particular, 6,6-congeners are key structural
features of a variety of natural products of biological interest.
In particular, spongistatins (altohyrtins), which were isolated
in 1993 by three research groups1 from marine sponges of
the genus Spongia, present two highly functionalized 6,6-
spiroketal subunits in their skeleton (Figure 1). The highly
potent antitumor activity of these compounds2 combined with
their impressive architectures and their extremely low natural
abundance prompted organic chemists to develop strategies
to face the synthetic challenge of their preparation. Several
total syntheses3 have been reported,4 and many routes to key
subunits have also been described.
In particular, considerable efforts have been devoted to
the efficient preparation of the axial/axial AB and axial/
equatorial CD spiroketals and on the EF tetrahydropyran
(1) (a) Pettit, G. R.; Cichacz, Z. A.; Gao, F.; Herald, C. L.; Boyd, M.
R.; Schmidt, J. M.; Hooper, J. N. A. J. Org. Chem. 1993, 58, 1302. (b)
Pettit, G. R.; Cichacz, Z. A.; Gao, F.; Herald, C. L.; Boyd, M. R. J. Chem.
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N.; Shinoda, K.; Matsunaga, S. J. Am. Chem. Soc. 1993, 115, 3977.
Figure 1. Altohyrtins and spongistatins.
fragment.5 Recently, a noniterative methodology has been
developed in our group for the asymmetric synthesis of C15
polyketides from readily available 2,2′-methylenedifuran.6
This method was applied to the synthesis of the polyol
10.1021/ol702326x CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/03/2007

AB spiroketal of spongistatins which was planned from
functionalized cycloheptene B through oxidative cleavage
of the olefin, selective reduction of the resulting aldehyde,
and spiroketalization under acidic conditions (Scheme 1).
Intermediate B should arise from enantiomerically pure diol
C that will be produced from 2,2′-methylenedifuran (1)
through a double [4 + 3]-cycloaddition followed by desym-
metrization of the meso bisadduct isomer.
Scheme 1. Retrosynthetic Plan
Difuryl derivative 1 was converted into diolefin meso-2
as previously reported,6a and desymmetrization of this
intermediate was achieved by Sharpless asymmetric dihy-
droxylation,9 in the presence of an enriched AD-mix-R, to
afford diol 3 with 98.4% ee (Scheme 2). The diastereoiso-
Scheme 2
subunit of the polyene macrolide antibiotic RK-3977 and to
the generation of C15 polyketide spiroketals.8
We report here a new application of this versatile meth-
odology to the synthesis of an advanced precursor A of the
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meric diol was isolated in 16% yield, but its enantiomeric
excess was only 4%.
A four-step sequence, involving methanolysis of the acetyl
groups, oxidative cleavage of the diol moiety, followed by
diastereoselective reduction of the oxo-aldehyde intermediate
under Evans conditions10 and selective silylation of the
primary alcohol, afforded triol (+)-4 with 80% overall yield.
5108
Org. Lett., Vol. 9, No. 24, 2007

Scheme 3. Spiroketalization
Transformation of the 1,3-anti-diol as the corresponding
to low discrimination between the two p-methoxy benzoate
moieties. In situ generated potassium isopropoxide was the
most efficient base and furnished alcohol (+)-7 in 78% yield
based on recovered starting material (brsm) (47% yield).
Triol (+)-8 was then obtained by acidic methanolysis of the
acetonide moiety.
acetonide and subsequent etherification of the remaining
secondary alcohol provided the orthogonally protected hexol
(+)-6 in 58% yield (two steps). At this stage, the selective
saponification of the C(4IV)-p-methoxy benzoate (PMBz) was
investigated. Several alcoholates were assayed (MeOK,
2-BuOK, 2,2-dimethyl-3-pentanolate, 3-pentanolate) but led
In a first series of attempts, ozonolysis of the olefin moiety
of (+)-8 followed by reductive treatment, first with dimethyl
sulfide then with K-selectride, afforded a 1:3 mixture of
linear ketone (-)-9 and hemiketal (-)-10, in 65% yield (three
steps, Scheme 3). Gratifyingly, when the crude mixture was
submitted to slow chromatography on silica gel, the linear
intermediate was fully isomerized to the hemiketal to furnish
(-)-10 in 82% yield (three steps). All attempts to perform
spiroketalization from the linear intermediate (-)-9 were not
met with success. Nevertheless, acidic treatment of (-)-10
with CSA allowed cyclization to the thermodynamic spiro-
ketal (-)-11 in 88% yield. Interestingly, the use of PPTS
for this step led to a separable mixture of the axial/axial
spiroketal (-)-11 and its equatorial/equatorial stereoisomer
(-)-12 (for conformational assignments, see Supporting
Information) in a 3:2 ratio (62% yield). Variation on the
nature of the acidic partner can therefore lead to different
stereomeric 6,6-spiroketals. The primary alcohol of (-)-11
was then selectively silylated to afford (-)-13. The structure
of the spiroketal was assigned on the basis of its 2D NOESY
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3
1H NMR spectrum. The JH,H coupling constants observed
for protons H-C(2′′), H-C(3′′), H-C(4′′), H-C(8′′),
H-C(9′′), and H-C(10′′) as well as diagnostic NOEs
[H-C(2′′)/H-C(4′′), H-C(8′′)/H-C(10′′)] established the
chair conformation of the two rings. NOEs between the pairs
of axial and equatorial H-C(5′′)/H-C(11′′) and cross-peaks
between the signals of H-C(2′′) and H-C(8′′) proved the
axial/axial conformation of the spiroketal.
(6) (a) Schwenter, M. E.; Vogel, P. Chem.sEur. J. 2000, 6, 4091. (b)
Schwenter, M. E.; Vogel, P. J. Org. Chem. 2001, 66, 7869. (c) Meilert, K.
M.; Schwenter, M. E.; Shatz, Y.; Dubbaka, S. R.; Vogel, P. J. Org. Chem.
2003, 68, 2964. (d) Vogel, P.; Gerber-Lemaire, S.; Carmona, A. T.; Meilert,
K. T.; Schwenter, M. E. Pure Appl. Chem. 2005, 77, 131.
(7) Gerber-Lemaire, S.; Carmona Asenjo, A. T.; Meilert, K.; Vogel, P.
Eur. J. Org. Chem. 2006, 891.
(8) Meilert, K.; Pettit, G. R.; Vogel, P. HelV. Chim. Acta 2004, 87, 1493.
(9) Kolb, H. C.; Van Nieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2488.
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1988, 110, 3560.
The functionalities of the AB spiroketal of spongistatins
were then introduced on the two rings (Scheme 4). Oxidation
of the alcohol at C(4′′) under Ley’s conditions11 followed
by diastereoselective equatorial addition of methyl magne-
Org. Lett., Vol. 9, No. 24, 2007
5109

Scheme 4
sium bromide led to the tertiary alcohol (-)-15. The
the previously reported diol 3, with an 8% overall yield and
through a sequence of highly diastereoselective transforma-
tions. This route requires the isolation of only 11 synthetic
intermediates. Further studies toward the preparation of the
CD spiroketal subunit are in progress in our laboratory. This
versatile methodology should also give access to a number
of analogues. Complete control of the chemoselective
functional modifications is possible as the ester belonging
to the cycloheptenyl moiety can be saponified more rapidly
than those belonging to the acyclic side chain.
stereogenic center at C(10′′) was installed by a sequence of
smooth cleavage of the p-methoxybenzyl ether in the
presence of DDQ, followed by oxidation of the resulting
secondary alcohol. A diastereoselective reduction through
equatorial addition of the hydride provided (-)-17 as a
single isomer and with a good yield (89%, three steps). A
final selective acetylation furnished (-)-18 which consti-
tutes a very advanced precursor of the AB spiroketal of
spongistatins.
The stereochemical assignments were confirmed through
1
analysis of the 2D NOESY H NMR spectrum of (-)-18.
Acknowledgment. This work was supported by the Swiss
National Foundation. We thank Mr. Martial Rey (NMR
spectroscopy service, ISIC, EPFL), Mr. Francesco Sepulveda,
and Dr. Alain Razaname (MS service, ISIC, EPFL) for
technical help.
Diagnostic NOEs [H-C(2′′)/HO-C(4′′)] established the
axial configuration of the tertiary alcohol at C(4′′).
Cross-peaks between the signals of the pairs of axial and
equatorial H-C(5′′)/H-C(11′′) as well as NOEs between
the signals of H-C(2′′) and H-C(8′′) indicated that the axial/
axial conformation of the spiroketal was maintained.
In summary, the synthesis of an advanced precursor of
the AB spiroketal of spongistatins has been achieved from
Supporting Information Available: Experimental pro-
1
cedures and full analytical data (including H, 13C, and 2D
spectra). This material is available free of charge via the
Internet at http://pubs.acs.org.
(11) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639.
OL702326X
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